Gene:

CYP2D6

cytochrome P450, family 2, subfamily D, polypeptide 6

Guidelines regarding the use of pharmacogenomic tests in dosing for codeine have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Download: article and supplement

Excerpt from the codeine dosing guidelines:

[The table below] summarizes the therapeutic recommendations for codeine based on CYP2D6 phenotype. A standard starting dose of codeine, as recommended in the product label, is warranted in patients with an extensive metabolizer phenotype (i.e., a CYP2D6 activity score of 1.0 to 2.0). Likewise, a standard starting dose of codeine is warranted in patients with an intermediate metabolizer phenotype (i.e., a CYP2D6 activity score of 0.5); these patients should be monitored closely for less than optimal response and should be offered an alternative analgesic if required. If the CYP2D6 substrate tramadol is selected as alternative therapy in intermediate metabolizers, close monitoring should be carried out because of the possibility of low response.

If clinical genotyping identifies a patient as a CYP2D6 poor metabolizer (i.e., a CYP2D6 activity score of 0), current evidence suggests that the use of codeine be avoided because of the possibility of lack of effect, and that an alternative analgesic should be used. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in poor metabolizers. There is insufficient evidence in the literature to recommend a higher dose of codeine in poor metabolizers, especially given that adverse effects do not differ between poor metabolizers and extensive metabolizers.

In a patient identified as a CYP2D6 ultrarapid metabolizer (i.e., a CYP2D6 activity score of >2.0), the choice of an alternative analgesic should be made to avoid the risk of severe toxicity associated with a "normal" dose of codeine. That is, it may be preferable to use an analgesic other than the CYP2D6 substrate tramadol in ultrarapid metabolizers.

*Frequency estimates are based on data from Caucasians and may differ substantially for other ethnicities. See Supplementary Data for estimates of phenotype frequencies among different ethnic/geographic groups.

**Note that some investigators define patients with an activity score of 0.5 and 1.0 as intermediate metabolizers and define patients with an activity score of 1.5 and 2.0 as extensive metabolizers. Classifying patients with an activity score of 1.0 as extensive metabolizers in this guideline is based on data specific for formation of morphine from codeine in these patients.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for amitriptyline based on CYP2D6 genotypes (PMID:21412232). They recommend selecting an alternative drug or reducing the initial dose for patients carrying intermediate metabolizer alleles and selecting alternative drugs or monitor amitypityline and nortriptyline plasma concentration for patients carrying the poor metabolizer or ultrarapid metabolizer alleles.

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Amitriptyline CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for aripiprazole based on CYP2D6 genotypes (PMID:21412232). They recommend reducing maximum dose for patients carrying poor metabolizer alleles of CYP2D6.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Aripiprazole CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for atomoxetine based on CYP2D6 genotypes (PMID:21412232).

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Atomoxetine CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for carvedilol based on CYP2D6 genotypes (PMID:21412232). They conclude that there are no recommendations at this time.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Carvedilol CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clomipramine based on CYP2D6 genotypes (PMID:21412232). They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and alternative drug for patients carrying the ultrarapid metabolizer (UM) allleles.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Clomipramine CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clozapine based on CYP2D6 genotypes (PMID:21412232). They conclude that there are no recommendations at this time.

• *See Methods or PMID: 18253145 for definition of "good quality."
• Please see attached PDF for detailed information about the evaluated studies: Clozapine CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for codeine based on CYP2D6 genotypes (PMID:21412232). They recommend alternative drug for analgesia for patients carrying the poor metabolizer (PM) alleles, intermediate metabolizer alleles and the ultrarapid metabolizer (UM) allleles.

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Codeine CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for doxepin based on CYP2D6 genotypes (PMID:21412232). They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and intermediate metabolizer alleles and alternative drug for patients carrying the ultrarapid metabolizer (UM) allleles.

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for duloxetine based on CYP2D6 genotypes (PMID:21412232). They conclude that there are no recommendations at this time.

• Please see attached PDF for detailed information about the evaluated studies: Duloxetine CYP2D6
• See Methods or PMID: 18253145 for more background information about the project.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flecainide based on CYP2D6 genotypes (PMID:21412232). They recommend lower dose for patients carrying the poor metabolizer (PM) alleles and intermediate metabolizer alleles.

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for flupenthixol based on CYP2D6 genotype (PMID:21412232). They did not find evidence for a gene-drug interaction and therefore provide no dosing recommendations at this time.

• See Methods or PMID: 18253145 for more background information about the project.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for haloperidol based on CYP2D6 genotype (PMID:21412232). They recommend dose reduction for poor metabolizer patients.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for imipramine based on CYP2D6 genotype (PMID:21412232). They recommend reducing the dose for poor and intermediate metabolizer patients, and selecting an alternative drug for ultra metabolizers.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Imipramine CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for metoprolol based on CYP2D6 genotype (PMID:21412232). They recommend either selecting another drug or dose reduction for poor and intermediate metabolizer patients, with dose titration for ultra metabolizers.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for mirtazapine based on CYP2D6 genotype (PMID:21412232). They do not provide dosing recommendations at this time.

• *See Methods or PMID: 18253145 for definition of "moderate" quality.
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for nortriptyline based on CYP2D6 genotype (PMID:21412232). They recommend reducing the dose for poor and intermediate metabolizer patients and selecting an alternative drug or increasing the dose for ultra metabolizers.

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Nortriptyline CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for olanzapine based on CYP2D6 genotype (PMID:21412232). They do not provide dosing recommendations at this time.

• *See Methods or PMID: 18253145 for definition of "moderate" quality.
• NS: not statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for oxycodone based on CYP2D6 genotype (PMID:21412232). They recommend using an alternate drug for poor, intermediate and ultra metabolizer patients.

• *See Methods or PMID: 18253145 for definition of "moderate" quality.
• S: statistically significant difference.
• NS: not statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for paroxetine based on CYP2D6 genotype (PMID:21412232). They suggest using an alternative drug for ultra metabolizers.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for propafenone based on CYP2D6 genotype (PMID:21412232). They suggest a reduced dose for poor metabolizers, and adjusting dose according to plasma concentrations or using an alternative drug for intermediate and ultrarapid metabolizers.

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for risperidone based on CYP2D6 genotypes (PMID:21412232). For all genotypes, they recommend selecting an alternative drug or being extra alert to Adverse Drug Events and adjusting dose to clinical response.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tamoxifen based on CYP2D6 genotypes (PMID:21412232). For PM and IM genotypes, they recommend considering using aromatase inhibitors for postmenopausal women due to increased risk for relapse of breast cancer with tamoxifen. For IM genotypes, they recommend avoiding concomitant CYP2D6 inhibitor use.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tramadol based on CYP2D6 genotypes (PMID:21412232). For PM and IM genotypes, they recommend selecting an alternative drug (not oxycodone or codeine) and/or being extra alert to symptoms of insufficient pain relief. For UM genotypes, they recommend using a 30% decreased dose and being alert for ADEs, or using an alternative drug (not oxycodone or codeine).

• *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• S: statistically significant difference.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for venlafaxine based on CYP2D6 genotypes (PMID:21412232). For PM and IM genotypes, they state that there are not sufficient data to allow calculation of dose adjustment, and they recommend selecting an alternative drug or adjusting dose to clinical response and monitoring (O-desmethyl)venlafaxine plasma concentration. For UM genotypes, they recommend titrating dose to a maximum of 150% of the normal dose(based on venlafaxine and (O-desmethyl)venlafaxine plasma concentration or selecting an alternative drug.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Venlafaxine CYP2D6

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for zuclopenthixol based on CYP2D6 genotypes (PMID:21412232). For PM genotypes, they recommend reducing dose by 50% or selecting an alternative drug. For IM genotypes, they recommend reducing dose by 25% or selecting an alternative drug. For UM genotypes, they state that there are insufficient data to allow calculation of dose adjustment, and to be alert to low zuclopenthixol plasma concentrations or to select an alternative drug.

• *See Methods or PMID: 18253145 for definition of "good quality."
• S: statistically significant difference.
• Please see attached PDF for detailed information about the evaluated studies: Zuclopenthixol CYP2D6

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Chlordiazepoxide and Amitriptyline.

Excerpt from the Chlordiazepoxide and Amitriptyline drug label:

"Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.
The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the type 1c antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Chlordiazepoxide and Amitriptyline drug label PDF.

Aripiprazole is an atypical antipsychotic medication mainly used for the treatment of schizophrenia. It is also indicated for the acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder and for an adjunctive therapy treatment to antidepressants for the treatment of major depressive disorder. The mechanism of action is unknown, but aripiprazole shows partial agonist activity at DRD2 and HTR1A receptors and antagonist activity at HTR2A receptors. Aripiprazole undergoes hepatic metabolization, primarily by the cytochrome P450 enzymes CYP3A4 and CYP2D6.

Excerpts from the Aripiprazole drug label:

"Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Coadministration of ABILIFY with known inhibitors of CYP2D6, such as quinidine or fluoxetine in EMs, approximately doubles aripiprazole plasma exposure, and dose adjustment is needed (see DRUG INTERACTIONS (7.1)). The mean elimination half-lives are about 75 hours and 146 hours for aripiprazole in EMs and PMs, respectively."

"Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg. quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels. Aripiprazole dose should be reduced to one-half of its normal dose when quinidine is given concomitantly with aripiprazole. Other significant inhibitors of CYP2D6, such as fluoxetine or paroxetine, would be expected to have similar effects and should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. "

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Aripiprazole drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Atomoxetine is a selective noradrenaline reuptake inhibitor. It is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder. The exact mechanism of action is unknown, but atomoxetine selectively inhibits the pre-synaptic noradrenaline transporter (SLC6A2), as determined in ex vivo studies. Atomoxetine is eliminated primarily through oxidative metabolism by CYP2D6 and subsequent glucuronidation.

Excerpts from the Atomoxetine drug label:

"Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of STRATTERA with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary."

"A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity (extensive metabolizers (EMs)). Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure."

"In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css,max is about 3- to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. "

"Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of STRATTERA may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Atomoxetine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Carvedilol is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, to reduce cardiovascular mortality in clinically stable patients with left ventricular dysfunction following myocardial infarction, and for the management of essential hypertension. It is a nonselective beta-adrenergic blocking agent with a1-blocking activity.
Carvedilol is a racemic mixture and undergoes stereoselective first-pass metabolism. Cytochrome P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, CYP2C19, CYP1A2, and CYP2E1.

Excerpts from the Carvedilol drug label:

"Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the a-blocking R(+) enantiomer."

"Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R( + )-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S( - )-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19)."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Carvedilol drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Cevimeline is a muscarinic agonist which binds to muscarinic receptors. Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögrens Syndrome. Cytochrome P450 enzymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline.
Excerpts from the Cevimeline drug label:

"Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Cevimeline drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Clomipramine.

PGx information can be found in the Drug Interactions label section.

Excerpts from the clomipramine (Anafranil) label:

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.

It is desirable to monitor TCA plasma levels whenever an agent of the tricyclic antidepressant class including Anafranil is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the clomipramine (Anafranil) drug label.

Clozapine is an atypical antipsychotic drug. It is approved for the treatment of severely ill patients with schizophrenia who fail to show an acceptable response to standard antipsychotic drug treatment. Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4.

Excerpts from the Clozapine drug label:

"A subset (3%-10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, the tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.
Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore, coadministration of clozapine with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Clozapine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Codeine is an opiod analgesic pro-drug, typically used for pain relief. It is metabolized by CYP2D6 into morphine, which is the active drug form. CYP2D6 poor and ultra-rapid metabolizers may experience different efficacy. Mothers who are ultra-rapid metabolizers and breast-feeding should be particularly aware of potential danger to breastfed infants.

Excerpts from the codeine sulfate drug label:

"Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing."

"Codeine is secreted into human milk...some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the codeine sulfate drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with desipramine.

Excerpt from the desipramine hydrochloride label:

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).

PGx information can be found in the Drug Interactions label section.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the desipramine drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with desloratadine and pseudoephedrine.

Excerpt from the desloratadine and pseudoephedrine (Clarinex-D) label:

"Data from clinical trials with desloratadine indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of desloratadine. In pharmacokinetic studies (n= 3748), approximately 6% of subjects were poor metabolizers of desloratadine (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or a subject with a desloratadine half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2 to 5 years, 1575 subjects aged 6 to 11 years, and 1196 subjects aged 12 to 70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1462) and Hispanics (2%, n=1063). The median exposure (AUC) to desloratadine in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of desloratadine cannot be prospectively identified and will be exposed to higher levels of desloratadine following dosing with the recommended dose of desloratadine. In multidose clinical safety studies, where metabolizer status was prospectively identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with CLARINEX Syrup for 15 to 35 days. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers. Although not seen in these studies, an increased risk of exposure-related adverse events in patients who are poor metabolizers cannot be ruled out."

PGx information can be found in the Clinical Pharmacology label section.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the desloratadine and pseudoephedrine (Clarinex-D) drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Dextromethorphan and Quinidine.

PGx information can be found in the Clinical Pharmacology and Warnings and Precautions label sections.

Excerpt from the dextromethorphan and quinidine (Nuedexta) label:

12.5 Pharmacogenomics
The quinidine component of NUEDEXTA is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be
achieved compared to when dextromethorphan is given alone. Approximately 7-10% of Caucasians and 3-8% of African Americans
generally lack the capacity to metabolize CYP2D6 substrates and are classified as PMs. The quinidine component of NUEDEXTA is
not expected to contribute to the effectiveness of NUEDEXTA in PMs, but adverse events of the quinidine are still possible. In those
patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered
prior to making the decision to treat with NUEDEXTA [see Concomitant Use of CYP2D6 Substrate (5.4), CYP2D6 Poor Metabolizer
(5.8), Pharmacokinetics (12.3)].

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the dextromethorphan and quinidine (Nuedexta) drug label.

Doxepin hydrochloride is a tricyclic psychotherapeutic agent (TCA). It is recommended for the treatment of psychoneurotic patients with depression and/or anxiety. Doxepin is primarily metabolized by CYP2D6.

Excerpts from the Doxepin drug label:

"The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA)."

"In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide)...Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 and CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors (SSRIs)) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Doxepin drug label PDF.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Galantamine.

PGx information can be found in the Special Populations label section.

Excerpts from the galantamine label:

Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism
of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly (see PRECAUTIONS, Drug-Drug Interactions). O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor
metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted
for most of the sample radioactivity.

Population pharmacokinetic analysis
indicated that there was a 25% decrease in median clearance in poor metabolizers compared to extensive metabolizers. Dosage
adjustment is not necessary in patients identified as poor metabolizers as the dose of drug is individually titrated to tolerability.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the galantamine drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Iloperidone.

PGx information can be found in the Clinical Pharmacology, Dosage and Administration, Drug Interactions, Specific Populations and Warnings and Precautions label sections.

Excerpts from the iloperidone (Fanapt) label:

The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23
hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively. Steady-state concentrations are attained
within 3-4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. The pharmacokinetics of
iloperidone is more than dose proportional. Elimination of iloperidone is mainly through hepatic metabolism involving two P450
isozymes, CYP2D6 and CYP3A4.

Co-administration of FANAPT with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3 fold increase in iloperidone plasma exposure, and therefore one-half of the FANAPT dose should be administered. Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one half.
Laboratory tests are available to identify CYP2D6 PMs.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the iloperidone (Fanapt) drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Imipramine.

PGx information can be found in the Drug Interactions label sections.

Excerpts from the imipramine label:

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the imipramine drug label.

Metoprolol is a selective beta1-adrenoreceptor blocking agent used for the treatment of hypertension, angina pectoris, and acute myocardial infarction. Metoprolol is metabolized by the cytochrome P450 enzymes in the liver with a major contribution of CYP2D6.

Excerpts from the Metoprolol drug label:
"The oxidative metabolism of Lopressor is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers. Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of Lopressor than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of Lopressor seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of Lopressor contribute significantly to its beta-blocking effect."

"Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Lopressor. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer (see Pharmacokinetics section). Caution should therefore be exercised when coadministering potent CYP2D6 inhibitors with Lopressor. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Metoprolol drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Nortriptyline.

PGx information can be found in the Drug Interactions label section.

Excerpt from the nortriptyline label:

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7% to 10% of caucasians are so calledpoor metabolizers. In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual
who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the nortriptyline drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Paroxetine.

PGx information can be found in the Clinical Pharmacology and Drug Interactions label sections.

Excerpts from the paroxetine label:

Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

Therefore, coadministration of paroxetine hydrochloride with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, tamoxifen and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the paroxetine drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Perphenazine.

PGx information can be found in the Clinical Pharmacology and Drug Interactions label sections.

Excerpts from the perphenazine label:

The pharmacokinetics of perphenazine covary with the hydroxylation of debrisoquine which is
mediated by cytochrome P450 2D6 (CYP 2D6) and thus is subject to genetic polymorphism, i.e., 7%-10% of Caucasians and a low percentage of Asians have little or no activity and are called "poor metabolizers". Poor metabolizers of CYP 2D6 will metabolize perphenazine more slowly and will experience higher concentrations compared with normal or "extensive" metabolizers.

Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects. In one study of 45 elderly patients suffering from dementia treated with perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the perphenazine drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Pimozide.

PGx information can be found in the Warnings, Precautions, Contraindications and Dosage and Administration label sections.

Excerpts from the pimozine (Orap) label:

Individuals with genetic variations resulting in poor CYP 2D6 metabolism (approximately 5 to 10% of the population) exhibit higher
pimozide concentrations than extensive CYP 2D6 metabolizers. The concentrations observed in poor CYP 2D6 metabolizers are
similar to those seen with strong CYP 2D6 inhibitors such as paroxetine. The time to achieve steady state pimozide concentrations is
expected to be longer (approximately 2 weeks) in poor CYP 2D6 metabolizers because of the prolonged half-life. Alternative dosing
strategies are recommended in patients who are genetically poor CYP 2D6 metabolizers

At doses above 0.05mg/kg/day, CYP2D6 genotyping should be performed. In poor CYP 2D6 metabolizers, ORAP doses should not exceed 0.05mg/kg/day, and doses should not be increased earlier than 14 days

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the pimozine (Orap) drug label.

Propafenone is used to treat cardiac arrhythmia, but should be used only if the condition is thought to be life-threatening.
Its metabolism is by CYP2D6,CYP3A4 and CYP1A2. The combination of propafenone, CYP3A4 inhibition and CYP2D6 inhibition or CYP2D6 genetic deficiency could be hazardous.

Excerpt from the propafenone drug label:

"Propafenone is metabolized by CYP2D6,CYP3A4,and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups. Drugs that inhibit these CYP pathways(such as desipramine,paroxetine,ritonavir,sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone."

"There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2-10 hours. These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2. In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Propafenone drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Propanolol is a beta-blocker which is used for treatment of various conditions including hypertension, angina pectoris and migraine.

Excerpt from the propanolol drug label:

"In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and naphthyloxyactic acid was significantly lower in EMs than PMs."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Propanolol drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Protriptyline hydrochloride is an antidepressant agent, while its mechanism of action in man is not known. Protriptyline belongs to the class of tricyclic antidepressants.

Excerpts from the Protriptyline drug label:

"The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquine hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers")."
" Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses."

"In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics, propafenone and flecainide)."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Protriptyline drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Quinidine is a Class I antiarrhythmic medication which inhibits CYP2D6.

Excerpt from the quinidine drug label:

"Quinidine is not metabolized by cytochrome P450IID6, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450IID6."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Quinidine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Risperidone is an atypical antipsychotic used in the treatment of schizophrenia, bipolar I disorder, and autism. CYP2D6 is important in its metabolism.

Excerpts from the risperidone drug label:

"Risperidone is metabolized to 9-hydroxyrisperidone by CYP2D6, an enzyme that is polymorphic in the population and that
can be inhibited by a variety of psychotropic and other drugs (see Clinical Pharmacology (12.3)). Drug interactions that reduce
the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the
concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n#70) does not
suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups
has been made."

"CYP2D6 is subject to genetic polymorphism (about 6% to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9- hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Risperidone drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Terbinafine is an antifungal drug used for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium). It is an inhibitor of CYP2D6.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Terbinafine.

Excerpts from the Terbinafine (Lamisil) drug label:
"Terbinafine is an inhibitor of CYP4502D6 isozyme and has an effect on metabolism of desipramine, cimetidine, fluconazole, cyclosporine, rifampin, and caffeine."

"There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between Lamisil Tablets and these changes has not been established."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Terbinafine (Lamisil) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Tetrabenazine is used to treat Huntington's Disease chorea. Its primary metabolites are metabolized mainly by CYP2D6, and people with CYP2D6 poor metabolizer genotypes should be treated with lower doses.

Excerpts from the tetrabenazine drug label:

"DOSAGE AND ADMINISTRATION). Patients should be genotyped for CYP2D6 prior to treatment with daily doses of tetrabenazine
over 50 mg (see WARNINGS - Laboratory Tests). Patients who are PMs should not be given daily doses greater than 50 mg."

"Before patients are given a daily dose of greater than 50 mg, they should be tested for the CYP2D6 gene to determine whether they
are poor metabolizers (PMs) or extensive or intermediate metabolizers (EMs or IMs). When a dose of tetrabenazine is given to PMs,
exposure will be substantially higher (about 3-fold for a-HTBZ and 9-fold for b-HTBZ) than it would be in EMs. The dosage should
therefore be adjusted according to a patient's CYP2D6 metabolizer status by limiting the dose to 50 mg in patients who are CYP2D6
poor metabolizers."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tetrabenazine drug label.

The FDA recommends, but does not require, genetic testing prior to initiating treatment with tetrabenazine.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Thioridazine is used to treat schizophrenic patients. It has potentially fatal effects on heart rythm and should only be used if other antipsychotic drugs are not effective or cause intolerable side effects. Its use is warned against in people with reduced CYP2D6 activity and hence, reduced clearance of the drug, as that increases the likelihood of the potential fatal effects.

Excerpts from the thioridazine drug label:

"Therefore, thioridazine is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who
are known to have a genetic defect leading to reduced levels of activity of P450 2D6."

"Certain circumstances may increase the risk of Torsades de pointes and/or sudden death in association with the use of drugs that
prolong the QTc interval, including 1) bradycardia, 2) hypokalemia, 3) concomitant use of other drugs that prolong the QTc interval,
4) presence of congenital prolongation of the QT interval, and 5) for thioridazine in particular, its use in patients with reduced activity
of P450 2D6 or its coadministration with drugs that may inhibit P450 2D6 or by some other mechanism interfere with the clearance of
thioridazine."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Thioridazine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Timolol is a non-selective beta adrenergic agonist applied to the eye to reduce intraocular pressure. It is metabolized via CYP2D6.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Timolol (Istalol).

Excerpt from the Timolol (Istalol) drug label:
"Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Timolol (Istalol) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Tiotropium is an inhaled long-acting, antimuscarinic agent for the treatment of chronic obstructive pulmonary disease (COPD). It inhibits the M3-receptors of the airway smooth muscle leading to bronchodilation. Although mostly excreted unchanged it may in some part be metabolized by CYP2D6 and CYP3A4.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Tiotropium.

Excerpt from the Tiotropium (Spiriva) drug label:
"In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tiotropium (Spiriva) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Tolterodine, is a competitive muscarinic receptor antagonist used for the treatment of overactive bladder. It is primarily metabolized by CYP2D6.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Tolterodine.

Excerpts from the Tolterodine (Detrol) drug label:
"The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite."

"Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite."

"In a study of the effect of tolterodine immediate release tablets on the QT interval (SeeCLINICAL PHARMACOLOGY, Cardiac Electrophysiology), the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). The effect of tolterodine 8mg/day was not as large as that observed after four days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped. These observations should be considered in clinical decisions to prescribe DETROL for patients with a known history of QT prolongation or patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications (see PRECAUTIONS, Drug Interactions). There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or DETROL LA."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tolterodine (Detrol) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Trimipramine.

Excerpt from the Trimipramine (Surmontil) drug label:

"Drugs Metabolized by P450 2D6

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Trimipramine drug label PDF.

Venlafaxine (Effexor) is an inhibitor of neuronal serotonin and norepinephrine reuptake and weak inhibitor of dopamine reuptake used in the treatment of depression.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Venlafaxine.

Excerpt from the Venlafaxine (Effexor) drug label:
"Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine ... was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups."

"CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Venlafaxine (Effexor) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Tramadol and Acetaminophen is a mixture of two analgesic drugs used to treat pain. Tramadol is an opioid and metabolized mainly via CYP2D6. Acetaminophen is mainly metabolized via glucuronidation.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Tramadol and Acetaminophen.

Excerpt from the Tramadol and Acetaminophen drug label:
"Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers", while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicates that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tramadol and Acetaminophen drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Citalopram.

PGx information can be found in the Drug Interactions and Warnings label sections.

Excerpts from the citalopram (Celexa) label:

CYP3A4 and 2C19 Inhibitors - In vitro studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism
of citalopram. However, coadministration of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not
significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of
a single enzyme may not appreciably decrease citalopram clearance.

In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of Celexa (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for
CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the
imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is
unknown. Nevertheless, caution is indicated in the coadministration of TCAs with Celexa.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the citalopram (Celexa) drug label.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). Fluoxetine is indicated for the treatment of major depressive disorder, obsessive compulsive disorder, bulimia nervosa, and panic disorder. Fluoxetine is metabolized by several cytochrome P450 enzymes with CYP2D6 being a major contributor. At the same time, fluoxetine is an inhibitor of CYP2D6 mediated reactions.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Fluoxetine.

Excerpts from the Fluoxetine drug label:
"Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.9)"

"Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued."

"Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Fluoxetine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Combined fluoxetine and olanzapine is a drug mixture used for the treatment of bipolar disorder and major depressive disorder. Fluoxetine is a selective serotonin reuptake inhibitor and metabolized by several cytochrome P450 enzymes with CYP2D6 being a major contributor (see Fluoxetine Pathway and CYP2D6 VIP for more details). Olanzepine is an atypical antipsychotic. Olanzepine is metabolized via CYP1A2 and clearance is influences by smoking (see CYP1A2 VIP for additional information).

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Fluoxetine and Olanzapine.

Excerpt from the Fluoxetine and Olanzapine (Symbyax) drug label:
"A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme CYP2D6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower."

"Fluoxetine inhibits the activity of CYP2D6 and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6 ... should be approached with caution."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Fluoxetine and Olanzapine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Excerpt from the gefitinib drug label:

"Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to gefitinib."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Gefitinib drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Modafinil.

PGx information can be found in the Drug Interactions label section.

Excerpts from the modafinil label:

Potential Interactions with Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes
In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when modafinil is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result (See Other Drugs, Cyclosporine above).
The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme
(e.g., S-warfarin and phenytoin). In a subsequent clinical study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the single-dose pharmacokinetics of warfarin when compared to placebo (See Other Drugs, Warfarin above).

In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with modafinil and may require dosage reduction and monitoring for toxicity.

Tricyclic antidepressants - CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the modafinil drug label.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Fluvoxamine.

PGx information can be found in the Drug Interactions label section.

Excerpts from the fluvoxamine label:

Based on a finding of substantial interactions of fluvoxamine with certain of these drugs (see later parts of this section and also WARNINGS for details) and limited in vitro data for the 3A4 isozyme, it appears that fluvoxamine inhibits the following isozymes
that are known to be involved in the metabolism of the listed drugs:
1A2, 2C9, 3A4, 2C19, Warfarin, Alprazolam, Omeprazole, Theophylline, Propranolol, Tizanidine. In vitro data suggest that fluvoxamine is a relatively weak inhibitor of the 2D6 isozyme.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the fluvoxamine drug label.